Vinicio de Jesus Perez MD

Publication Details

  • Loss-of BMPR2 is Associated With Abnormal DNA Repair in Pulmonary Arterial Hypertension. American journal of respiratory cell and molecular biology Li, M., Vattulainen, S., Aho, J., Orcholski, M., Rojas, V., Yuan, K., Helenius, M., Taimen, P., Myllykangas, S., De Jesus Perez, V., Koskenvuo, J. W., Alastalo, T. P. 2014


    Rationale: Occlusive vasculopathy with intimal hyperplasia and plexogenic arteriopathy are severe histopathological changes characteristic for pulmonary arterial hypertension (PAH). While a phenotypic switch in pulmonary endothelial cells (EC) has been suggested to play a critical role in the formation of occlusive lesions, the pathobiology of this process is poorly understood. The goal was to identify novel molecular mechanisms associated with EC dysfunction and PAH-associated bone morphogenetic protein receptor 2 (BMPR2) deficiency during PAH pathogenesis. Methods: Bioinfomatics approach, patient samples and in vitro experiments were utilized. Results: By combining a meta-analysis of human iPAH-associated gene-expression microarrays and a unique gene expression profiling technique in rat endothelium, our bioinformatics approach revealed a PAH-associated dysregulation of genes involving chromatin organization, DNA metabolism, and repair. Our hypothesis that altered DNA repair and loss-of genomic stability play a role in PAH was supported by in vitro assays where pulmonary ECs from iPAH patients and BMPR2-deficient ECs were highly susceptible to DNA damage. Furthermore, we showed that BMPR2 expression is tightly linked to DNA damage control as excessive DNA damage leads to rapid down-regulation of BMPR2 expression. Moreover, we identified BRCA1 as a novel target for BMPR2 signaling and a novel modulator of pulmonary EC homeostasis. Conclusions: We show here that BMPR2 signaling plays a critical role in the regulation of genomic integrity in pulmonary ECs via genes such as BRCA1. We propose that iPAH-associated EC dysfunction and genomic instability are mediated through BMPR2 deficiency-associated loss of DNA damage control.

    View details for DOI 10.1165/rcmb.2013-0349OC

    View details for PubMedID 24433082

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